1. Field of the invention
The present invention is directed toward balancing the uricosuric and diuretic properties of indacrinone, a racemic compound, through a process which enables the proportion of its (+) and (-) enantiomers to be manipulated.
There continues to be a great deal of interest in the discovery and development of diuretics which are also uricosuric, since many currently available diuretics commonly lead to urate retention, hyperuricemia, and, occasionally, attacks of gout. Hyperuricemia, in turn, may itself be a risk factor for the development of cardiovascular disease, carbohydrate intolerance, and urate-induced nephropathy. A large percentage of hypertensive patients also have hyperuricemia.
For example, ticrynafen, or tienilic acid, produces a prompt diuresis with an increased excretion of sodium and chloride, while at maximal drug effect, uric acid clearance increases about five-fold. Although this drug was approved for use as an antihypertensive agent in the U.S. in 1979, it was later withdrawn when unacceptably high incidences of hepatotoxicity were revealed.
Uric acid transport by the renal tubules involves both readsorptive and secretory processes. There has been an interest in the mechanism of action of drugs that directly influence tubular transport 29stems for uric acid and thus alter the rate of uric acid excretion. Probenecid, for example, increases the urinary excretion of uric acid by inhibition of carrier-mediated reabsorption. Likewise, indacrinone or indacrynic acid, which is the subject of the present invention, inhibits urate reabsorption in the proximal tubule.
The action of uricosuric agents is often seemingly contradictory, because of the complexity of the transport mechanisms involved. Thus, increase, decrease, or lack of effect on the excretion of uric acid is not only highly species dependent, but dosage dependent as well. Moreover, depending on the exact conditions, the combined effect of two uricosuric drugs may be either additive or antagonistic.
The renal transport of uric acid in mammals involves both secretion and reabsorption. However, in man the process of reabsorption dominates so that the amount that is excreted is but a small fraction of that which is filtered. A variety of factors, including uricosuric drugs, can influence the relative importance of these bidirectional transport mechanisms in man. As also indicated above, uric acid is transported by carrier-mediated mechanisms, not by diffusion and in man the site of transport is located in the proximal tubule, including both the convoluted and straight portions.
2. Brief Description of the Prior Art
It should be noted that in the biomedical literature, "indacrinone" is most frequently employed as a generic name, although it is also used to refer to the racemic mixture. As a racemic mixture, and as the (+) or (-) enantiomer, "indacrinone" is disclosed in U.S. Pat. No. 4,096,267 by its chemical name: [(6,7-dichlore-2,3-dihydro-2-methyl-1-oxo-2-phenyl-1H-inden-5-yl) oxy]acetic acid. This patent also refers generally to the possibility of combining different indanones disclosed where greater diuretic activity and greater uricosuric activity are possessed by said indanones. However, this patent does not suggest manipulation of the proportion of (+) and (-) enantiomers of indacrinone within critical limits, for careful balancing of uricosuric and diuretic properties to give maximum therapeutic benefit.
The different pharmacodynamic effects of the (+) and (-) enantiomers of indacrinone, specifically that the principal saluretic activity of indacrinone resides in the (-) enantiomer while uricosuric activity is present in both (-) and (+) enantiomers, are described by Irvin et al., Clin. Pharmacol. Ther., p. 260 (Feb. 1980); deSolms et al., J. Med. Chem., Vol. 21, No. 5, pp. 437-443 (1978); and Woltersdorf et al. ACS Symposium Series No. 83 Diuretic Agents, pp. 219-220 (1978). These publications also do not suggest manipulation of the proportion of (+) and (-) enantiomers of indacrinone within critical limits so as to achieve the maximum therapeutic benefit from balanced uricosuric and diuretic properties, as is the case with the present invention.
British Pat. No. 1,475,177 discloses the combination of indacrinone racemic mixture or the (-) enantiomer of indacrinone with a potassium-sparing pyrazinoylguanidine diuretic, especially amiloride. However, this patent does not disclose or suggest a manipulated proportion of (+) and (-) enantiomers of indacrinone, or the combination of such a manipulated proportion with amiloride or other pyrazinoylguanidine diuretics.
U.S. Pat. No. 4,087,542 discloses the diuretic (+) isomer and uricosuric (-) isomer of 6,7-dichloro-2,3-dihydro-5-(2-thienyl)benzofuran-2-carboxylic acid and manipulating the ratio of these isomers to achieve a balance of diuretic and uricosuric properties. However, manipulation of these isomers requires total separation of the diuretic and uricosuric activity between the two isomers so that the manipulation of these isomers is not suggestive of the possibility of manipulating the (+) and (-) enantiomers of indacrinone, a wholly different compound. Furthermore, there is no known currently marketed or experimental drug in which a ratio of enantiomers, other than the synthetically occurring 50:50, is used.
U.S. Pat. Nos. 4,177,285 and 4,182,764 disclose [1-oxo-2-aryl or thienyl-2-substituted-5-indanyloxy (or thio)]alkanoic acids and derivatives thereof and methods for separating the optically active isomers from racemic mixtures of these compounds by using an optically active base. There is no suggestion in these patents of manipulating the (+) and (-) enantiomers of such compounds.
Efficient, asymmetric alkylation reactions have been a goal long sought after in organic synthesis. The recent literature [S. Hashimoto, et al., Tet. Lett., 573-76 (1978); A. I. Meyers, et al., J. Am. Chem. Soc., 103, 3081-87 (1981); D. Enders, Chemtech, 504-13 (1981); and, K. Saigo, et al., Bull. Chem. Soc. Jap, 52, 3119 (1979)]reports three-step sequences to achieve such a goal in high enantiomeric excesses (i.e., e.e.s) via: 1) reaction of a substrate with a chiral molecule to produce a new, modified chiral substrate molecule; 2) alkylation of the new, modified chiral substrate molecule; and, 3) subsequent reaction to liberate the desired chiral alkylated substrate and regenerate the original chiral molecule. Although high e.e.s can be achieved by these procedures, they are long, complex, and require the use of stoichiometric quantities of a chiral molecule.
Chiral phase transfer mediated alkylations offer a potentially simple, one-step solution to this problem. J. C. Fiaud [Tet. Lett., 3495-96 (1975)]reports the first attempt at such using cyclic .beta.-ketoesters as substrates and an ephedrinium bromide as a catalyst. Enantiomeric excesses (e.e.s) of 15% were claimed by Fiaud using his procedures. Enantiomeric excesses of this magnitude are considered to be insignificant from the aspect of useful chiral catalysts. Regardless, E. V. Dermlow, et al. [J. Chem. Res.,(S), 292-293 (1981)]later established that Fiaud's claimed e.e.s were non-existent under the conditions reported.
Indacrinone, which is a 50:50 mixture of the (+) and (-) enantiomers of [(6,7-dichloro-2,3-dihydro-2-methyl-l-oxo-2-phenyl-1H-inden-5-yl) oxy]acetic acid [hereinafter referred to and identified as indenyloxy acetic acid], is a potent, high ceiling diuretic.
The (+) and (-) enantiomers of idenyl-oxy acetic acid are represented by the formulae: ##STR1##
The idenyl-oxy acetic acid compound is a racemic mixture of these enantiomers, and methods for its preparation are described in U.S. Pat. No. 4,096,267. Methods for resolving the racemic mixture into its (+) and (-) enantiomers are also described in said patent, as well as in deSolms et al., J. Med. Chem., Vol. 21, No. 5, pp. 437-443 (1978).
As mentioned earlier, diuretics are valuable therapeutic agents useful in the treatment of cardiovascular and renal diseases, for example in the management of all types and grades of severity of congestive heart failure and in the treatment of mild, moderate, and severe forms of hypertension. As a result of the loss of water and electrolyte, dramatic improvement is noted in peripheral and pulmonary edema, dyspnea, orthopnea, ascites and pleural effusion. Diuretics also provide effective therapy in various forms of renal edema, for example, edema associated with nephrosis and certain types of nephritis. Their administration results in prompt excretion of retained fluid and electrolytes, especially sodium chloride.
In addition to its potent diuretic and saluretic properties, this idenyl-oxy acetic acid compound also possesses important uricosuric properties as well. However, this uricosuric activity presents a complex picture, as will be apparent from the following discussion.
(1) Both enantiomers of idenyl-oxy acetic acid possess uricosuric activity. The (-) enantiomer, which is 20 to 40 times more potent than the (+) enantiomer as a natriuretic agent, possesses uricosuric activity on an acute basis; i.e., within the first few hours of administration, but on a chronic basis, produces hyperuricemia. The uricosuric activity seen on an acute basis is considered to result from the increased flow of water through the renal tubule produced by the (-) enantiomer together with somewhat decreased reabsorption of urate produced by blockade of that reabsorption by the (-) enantiomer. As the acute phase passes and administration of the (-) enantiomer becomes chronic, a decrease in the extracellular fluid volume results which produces a significantly enhanced rate of urate reabsorption. Thus, as the extracellular fluid volume becomes depleted, uricosuria ceases and urate reabsorption increases to the point that hyperuricemia results.
Both the (-) and (+) enantiomers have significant intrinsic uricosuric activity; and it seems probable that they both act on the same site or sites in the proximal portion of the renal tubule which regulate urate reabsorption. When the (-) enantiomer is administered by itself, or when a racemic mixture of (-) and (+) enantiomers is administered, the final result or net effect will be hyperuricemia, since the higher natriuretic potency of the (-) enantiomer overcomes the urate reabsorption inhibitory potency of both the (-) and (+) enantiomers through the mechanism of extracellular fluid depletion, as explained above.
(2) Both the (+) and (-) enantiomers of idenyl-oxy acetic acid possess natriuretic properties. As mentioned above, the (-) enantiomer is significantly more potent as a natriuretic agent than the (+) enantiomer. However, the (+) enantiomer does have modest potency as a natriuretic agent which, again, further complicates the problem of manipulating the proportion of (+) and (-) enantiomers in order to achieve a balance of diuretic and uricosuric properties.
(3) There is no currently known practical way of reliably associating the degree of extracellular fluid volume depletion, which leads to hyperuricemia, with the extent of urate reabsorption inhibition, which results in uricosuria.
(4) The (+) enantiomer is considered to have a different site of action in the renal tubule from that of the (-) enantiomer, with correspondingly different therapeutic effects. (These sites of action and therapeutic effects are to be distinguished from the urate reabsorption regulation which occurs in the proximal renal tubule for both enantiomers, as already explained above.) The natriuretic activity of the (-) enantiomer is considered to be effected in the ascending limb of Henle's loop portion of the renal tubule. The (+) enantiomer, on the other hand, probably expresses its therapeutic effects in a more distal portion of the renal tubule.
(5) Uricosuric activity is only desirable in the context of avoiding hyperuricemia and its consequences. Since there is no known advantage to a hypouricemic state and since extensive uricosuria occasionally causes urate precipitation in renal tubules, the goal of manipulating the proportion of (+) and (-) enantiomers is to achieve, as nearly as possible, an isouricemic or slightly hypouricemic state; that is, administration of the indacrinone final product should result in neither a rise nor a large fall in patient serum uric acid levels.
As used in this context, the term "slightly hypouricemic" means a decrease in serum or plasma uric acid levels of 20% or less from the starting level for a particular patient, or from the mean starting level for a group of patients. The starting level may be a "normal" level of uric acid or it may be a "hyperuricemic" level. It is important to avoid hypouricemia of a greater extent than that indicated, since it is thought that it can result in acute rena
d by tubular urate precipitation. Thus, use of ticrynafen can cause a decrease in plasma uric acid levels of as high as 40%, which is considered undesirably high.